1. Field of the Invention
This invention relates to compounds that are inhibitors of intestinal apical membrane Na/phosphate co-transportation, medications containing these compounds, and methods for inhibiting sodium-mediated phosphate uptake, reducing serum PTH, calcium, calcitriol, and phosphate, and treating renal disease with these compounds and medications containing them.
2. Description of the Related Art
In 1995, 260,000 people with end-stage renal disease were being treated in this country at a Medicare cost of $9 billion. Another 500,000 people were diagnosed with chronic renal failure. Increasing the time for progression from chronic renal failure to end-stage renal failure by control of serum PTH, calcium, calcitriol, and phosphate, while improving patient nutritional status, would drastically reduce the projected cost of the 500,000 patients progressing to end-stage renal failure and improve the survival of those undergoing dialysis.
However, the medications currently available are less than adequate to address these problems. It would be desirable to develop medications capable of controlling serum PTH, calcium, calcitriol, and phosphate.
In a first aspect, this invention provides compounds of formula (I): 
where:
A1 and A2 are the same or different aryl groups collectively bearing at least one hydrophilic substituent;
E1 and E2 are the same or different and are O, S, or NR2 (where R2 is a linear or branched C1-C20 carbon containing group);
M is H or a pharmaceutically acceptable monovalent cation;
R1 is a linear or branched, saturated or unsaturated, C1-C20 carbon containing group;
Z is a single bond, a carbonyl, CE3E4, or CR3E3, where
E3 and E4 are the same or different and are OR4, SR4, or NR42, where
R3 is a linear or branched C1-C20 carbon containing group, and
R is H or a linear or branched C1-C20 carbon containing group; and
n is 0 or 1, or a pharmaceutically acceptable salt thereof, provided that the compound is not 4xe2x80x2-phosphophloretin or a pharmaceutically acceptable salt thereof.
These compounds are hydrophilic aryl phosphate, thiophosphate, and aminophosphate intestinal apical membrane Na-mediated phosphate co-transportation inhibitors; and are useful for inhibiting sodium-mediated phosphate uptake, reducing serum PTH, calcium, calcitriol, and phosphate, and treating renal disease.
In a second aspect, this invention provides a medication including a therapeutically effective amount of at least one compound of formula (I) or 4xe2x80x2-phosphophloretin in a suitable carrier.
In a third aspect, this invention provides a method of inhibiting sodium-mediated phosphate uptake, reducing serum PTH, calcium, calcitriol, and phosphate, and treating renal disease in an animal, including a human, by administering to that animal a therapeutically effective amount of at least one compound of formula (I) or 4xe2x80x2-phosphophloretin, or a medication containing it.